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Genotype and Gene Expression Associations with Immune Function in


It is now well established that natural populations of Drosophila melanogaster harbor substantial genetic variation associated with physiological measures of immune function. In no case, however, have intermediate measures of immune function, such as transcriptional activity of immune-related genes, been tested as mediators of phenotypic variation in immunity. In this study, we measured bacterial load sustained after infection of D. melanogaster with Serratia marcescens, Providencia rettgeri, Enterococcus faecalis, and Lactococcus lactis in a panel of 94 third-chromosome substitution lines. We also measured transcriptional levels of 329 immune-related genes eight hours after infection with E. faecalis and S. marcescens in lines from the phenotypic tails of the test panel. We genotyped the substitution lines at 137 polymorphic markers distributed across 25 genes in order to test for statistical associations among genotype, bacterial load, and transcriptional dynamics. We find that genetic polymorphisms in the pathogen recognition genes (and particularly in PGRP-LC, GNBP1, and GNBP2) are most significantly associated with variation in bacterial load. We also find that overall transcriptional induction of effector proteins is a significant predictor of bacterial load after infection with E. faecalis, and that a marker upstream of the recognition gene PGRP-SD is statistically associated with variation in both bacterial load and transcriptional induction of effector proteins. These results show that polymorphism in genes near the top of the immune system signaling cascade can have a disproportionate effect on organismal phenotype due to the amplification of minor effects through the cascade.


Vyšlo v časopise: Genotype and Gene Expression Associations with Immune Function in. PLoS Genet 6(1): e32767. doi:10.1371/journal.pgen.1000797
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000797

Souhrn

It is now well established that natural populations of Drosophila melanogaster harbor substantial genetic variation associated with physiological measures of immune function. In no case, however, have intermediate measures of immune function, such as transcriptional activity of immune-related genes, been tested as mediators of phenotypic variation in immunity. In this study, we measured bacterial load sustained after infection of D. melanogaster with Serratia marcescens, Providencia rettgeri, Enterococcus faecalis, and Lactococcus lactis in a panel of 94 third-chromosome substitution lines. We also measured transcriptional levels of 329 immune-related genes eight hours after infection with E. faecalis and S. marcescens in lines from the phenotypic tails of the test panel. We genotyped the substitution lines at 137 polymorphic markers distributed across 25 genes in order to test for statistical associations among genotype, bacterial load, and transcriptional dynamics. We find that genetic polymorphisms in the pathogen recognition genes (and particularly in PGRP-LC, GNBP1, and GNBP2) are most significantly associated with variation in bacterial load. We also find that overall transcriptional induction of effector proteins is a significant predictor of bacterial load after infection with E. faecalis, and that a marker upstream of the recognition gene PGRP-SD is statistically associated with variation in both bacterial load and transcriptional induction of effector proteins. These results show that polymorphism in genes near the top of the immune system signaling cascade can have a disproportionate effect on organismal phenotype due to the amplification of minor effects through the cascade.


Zdroje

1. LemaitreB

HoffmannJ

2007 The host defense of Drosophila melanogaster. Annual Review of Immunology 25 697 743

2. LazzaroBP

SacktonTB

ClarkAG

2006 Genetic variation in Drosophila melanogaster resistance to infection: a comparison across bacteria. Genetics 174 1539 1554

3. LazzaroBP

SceurmanBK

ClarkAG

2004 Genetic basis of natural variation in D. melanogaster antibacterial immunity. Science 303 1873 1876

4. TinsleyMC

BlanfordS

JigginsFM

2006 Genetic variation in Drosophila melanogaster pathogen susceptibility. Parasitology 132 767 773

5. Passador-GurgelG

HsiehW-P

HuntP

DeightonN

GibsonG

2007 Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster. Nature genetics 39 264 268

6. DrnevichJM

ReedyMM

RuediEA

Rodriguez-ZasS

HughesKA

2004 Quantitative evolutionary genomics: differential gene expression and male reproductive success in Drosophila melanogaster. Proceedings Biological sciences 271 2267 2273

7. CoffmanCJ

WayneML

NuzhdinSV

HigginsLA

McIntyreLM

2005 Identification of co-regulated transcripts affecting male body size in Drosophila. Genome biology 6 R53 R53

8. EdwardsAC

RollmannSM

MorganTJ

MackayTFC

2006 Quantitative genomics of aggressive behavior in Drosophila melanogaster. PLoS Genet 2 e154 doi:10.1371/journal.pgen.0020154

9. JordanKW

CarboneMA

YamamotoA

MorganTJ

MackayTFC

2007 Quantitative genomics of locomotor behavior in Drosophila melanogaster. Genome biology 8 R172 R172

10. FiumeraAC

DumontBL

ClarkAG

2005 Sperm competitive ability in Drosophila melanogaster associated with variation in male reproductive proteins. Genetics 169 243 257

11. HarbisonST

ChangS

KamdarKP

MackayTFC

2005 Quantitative genomics of starvation stress resistance in Drosophila. Genome biology 6 R36 R36

12. ChoeK-M

WernerT

StövenS

HultmarkD

AndersonKV

2002 Requirement for a peptidoglycan recognition protein (PGRP) in Relish activation and antibacterial immune responses in Drosophila. Science 296 359 362

13. GobertV

GottarM

MatskevichAA

RutschmannS

RoyetJ

2003 Dual activation of the Drosophila toll pathway by two pattern recognition receptors. Science 302 2126 2130

14. WernerT

Borge-RenbergK

MellrothP

SteinerH

HultmarkD

2003 Functional diversity of the Drosophila PGRP-LC gene cluster in the response to lipopolysaccharide and peptidoglycan. The Journal of biological chemistry 278 26319 26322

15. De GregorioE

SpellmanPT

TzouP

RubinGM

LemaitreB

2002 The Toll and Imd pathways are the major regulators of the immune response in Drosophila. The EMBO journal 21 2568 2579

16. LemaitreB

ReichhartJM

HoffmannJA

1997 Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proceedings of the National Academy of Sciences of the United States of America 94 14614 14619

17. Hedengren-OlcottM

OlcottMC

MooneyDT

EkengrenS

GellerBL

2004 Differential activation of the NF-kappaB-like factors Relish and Dif in Drosophila melanogaster by fungi and Gram-positive bacteria. The Journal of biological chemistry 279 21121 21127

18. TanjiT

HuX

WeberANR

IpYT

2007 Toll and IMD pathways synergistically activate an innate immune response in Drosophila melanogaster. Molecular and cellular biology 27 4578 4588

19. AgaisseH

PerrimonN

2004 The roles of JAK/STAT signaling in Drosophila immune responses. Immunological reviews 198 72 82

20. BoutrosM

AgaisseH

PerrimonN

2002 Sequential activation of signaling pathways during innate immune responses in Drosophila. Developmental cell 3 711 722

21. ImlerJ-L

BuletP

2005 Antimicrobial peptides in Drosophila: structures, activities and gene regulation. Chemical immunology and allergy 86 1 21

22. McKeanKA

NunneyL

2005 Bateman's principle and immunity: phenotypically plastic reproductive strategies predict changes in immunological sex differences. Evolution; international journal of organic evolution 59 1510 1517

23. RolffJ

2002 Bateman's principle and immunity. Proceedings Biological sciences 269 867 872

24. ZukM

1990 Reproductive strategies and disease susceptibility: an evolutionary viewpoint. Parasitology today 6 231 233

25. MackayTFC

2004 The genetic architecture of quantitative traits: lessons from Drosophila. Current opinion in genetics & development 14 253 257

26. Hill-BurnsEM

ClarkAG

2009 X-linked Variation in Immune Response in Drosophila melanogaster. Genetics Oct 12 [Epub ahead of print]

27. EmilssonV

ThorleifssonG

ZhangB

LeonardsonAS

ZinkF

2008 Genetics of gene expression and its effect on disease. Nature 452 423 428

28. EvansCJ

HartensteinV

BanerjeeU

2003 Thicker than blood: conserved mechanisms in Drosophila and vertebrate hematopoiesis. Developmental cell 5 673 690

29. LuoH

RosePE

RobertsTM

DearolfCR

2002 The Hopscotch Jak kinase requires the Raf pathway to promote blood cell activation and differentiation in Drosophila. Molecular genetics and genomics: MGG 267 57 63

30. SamakovlisC

KimbrellDA

KylstenP

EngströmA

HultmarkD

1990 The immune response in Drosophila: pattern of cecropin expression and biological activity. The EMBO journal 9 2969 2976

31. NehmeNT

LiégeoisS

KeleB

GiammarinaroP

PradelE

2007 A model of bacterial intestinal infections in Drosophila melanogaster. PLoS Pathog 3 e173 doi:10.1371/journal.ppat.0030173

32. BischoffV

VignalCc

BonecaIG

MichelT

HoffmannJA

2004 Function of the Drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria. Nature immunology 5 1175 1180

33. LynchM

WalshB

1998 Genetics and Analysis of Quantitative Traits: Sinauer Associates. 980

34. WentzellAM

RoweHC

HansenBG

TicconiC

HalkierBA

2007 Linking metabolic QTLs with network and cis-eQTLs controlling biosynthetic pathways. PLoS Genet 3 e162 doi:10.1371/journal.pgen.0030162

35. Pili-FlouryS

LeulierFo

TakahashiK

SaigoK

SamainE

2004 In vivo RNA interference analysis reveals an unexpected role for GNBP1 in the defense against Gram-positive bacterial infection in Drosophila adults. The Journal of biological chemistry 279 12848 12853

36. WangL

WeberANR

AtilanoML

FilipeSR

GayNJ

2006 Sensing of Gram-positive bacteria in Drosophila: GNBP1 is needed to process and present peptidoglycan to PGRP-SA. The EMBO journal 25 5005 5014

37. ChoeK-M

LeeH

AndersonKV

2005 Drosophila peptidoglycan recognition protein LC (PGRP-LC) acts as a signal-transducing innate immune receptor. Proceedings of the National Academy of Sciences of the United States of America 102 1122 1126

38. GottarM

GobertV

MichelT

BelvinM

DuykG

2002 The Drosophila immune response against Gram-negative bacteria is mediated by a peptidoglycan recognition protein. Nature 416 640 644

39. RämetM

ManfruelliP

PearsonA

Mathey-PrevotB

EzekowitzRAB

2002 Functional genomic analysis of phagocytosis and identification of a Drosophila receptor for E. coli. Nature 416 644 648

40. TanjiT

HuX

WeberAN

IpYT

2007 Toll and IMD pathways synergistically activate an innate immune response in Drosophila melanogaster. Mol Cell Biol 27 4578 4588

41. TzouP

ReichhartJ-M

LemaitreB

2002 Constitutive expression of a single antimicrobial peptide can restore wild-type resistance to infection in immunodeficient Drosophila mutants. Proceedings of the National Academy of Sciences of the United States of America 99 2152 2157

42. SacktonTB

LazzaroBP

SchlenkeTA

EvansJD

HultmarkD

2007 Dynamic evolution of the innate immune system in Drosophila. Nature genetics 39 1461 1468

43. LazzaroBP

2008 Natural selection on the Drosophila antimicrobial immune system. Curr Opin Microbiol 11 284 289

44. JigginsFM

KimKW

2005 The evolution of antifungal peptides in Drosophila. Genetics 171 1847 1859

45. SchlenkeTA

BegunDJ

2003 Natural selection drives Drosophila immune system evolution. Genetics 164 1471 1480

46. FiumeraAC

DumontBL

ClarkAG

2007 Associations between sperm competition and natural variation in male reproductive genes on the third chromosome of Drosophila melanogaster. Genetics 176 1245 1260

47. JunejaP

LazzaroBP

2009 Providencia sneebia sp. nov. and Providencia burhodogranariea sp. nov., isolated from wild Drosophila melanogaster. Int J Syst Evol Microbiol 59 1108 1111

48. LazzaroBP

SceurmanBK

CarneySL

ClarkAG

2002 fRFLP and fAFLP: medium-throughput genotyping by fluorescently post-labeling restriction digestion. BioTechniques 33 539 540, 542, 545–536

49. AyresJS

FreitagN

SchneiderDS

2008 Identification of Drosophila mutants altering defense of and endurance to Listeria monocytogenes infection. Genetics 178 1807 1815

50. Corby-HarrisV

HabelKE

AliFG

PromislowDE

2007 Alternative measures of response to Pseudomonas aeruginosa infection in Drosophila melanogaster. J Evol Biol 20 526 533

51. ReadAF

GrahamAL

RabergL

2008 Animal defenses against infectious agents: is damage control more important than pathogen control. PLoS Biol 6 e1000004 doi:10.1371/journal.pbio.1000004

52. AyresJS

SchneiderDS

2008 A signaling protease required for melanization in Drosophila affects resistance and tolerance of infections. PLoS Biol 6 e305 doi:10.1371/journal.pbio.0060305

53. De GregorioE

SpellmanPT

RubinGM

LemaitreB

2001 Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays. Proceedings of the National Academy of Sciences of the United States of America 98 12590 12595

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